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Abstract:

The present invention relates to a stable tablet comprising a
4,5-epoxymorphinan derivative or a pharmacologically acceptable acid
addition salt thereof as an effective ingredient. That is, the tablet
according to the present invention comprises: (1) as the effective
ingredient, a specific 4,5-epoxymorphinan derivative or a
pharmacologically acceptable acid addition salt; (2) sodium thiosulfate;
(3) at least one selected from the group consisting of saccharides and
sugar alcohols; and (4) crospovidone, sodium carboxymethyl starch or a
mixture thereof, in which tablet the content of the aforementioned (4) is
1 to 20% by weight per unit weight containing the aforementioned
effective ingredient.

Claims:

1. A tablet comprising the following (1) to (4): (1) as an effective
ingredient, a 4,5-epoxymorphinan derivative represented by the Formula
(I): ##STR00005## [wherein, the double line composed of a dashed line
and a solid line represents a double bond or a single bond; R1
represents C1-C5 alkyl, C4-C7 cycloalkylalkyl,
C5-C7 cycloalkenylalkyl, C6-C12 aryl,
C7-C13 aralkyl, C4-C7 alkenyl, allyl, C1-C5
furan-2-ylalkyl or C1-C5 thiophen-2-ylalkyl; R2 represents
hydrogen, hydroxy, nitro, C1-C5 alkanoyloxy, C1-C5
alkoxy, C1-C5 alkyl or --NR7R8; R7 represents
hydrogen or C1-C5 alkyl; R8 represents hydrogen,
C1-C5 alkyl or --C(═O)R9; R9 represents hydrogen,
phenyl or C1-C5 alkyl; R3 represents hydrogen, hydroxy,
C1-C5 alkanoyloxy or C1-C5 alkoxy; A represents
--N(R4)C(═X)--, --N(R4)C(═X)Y--, --N(R4)-- or
--N(R4)SO2-- (wherein X and Y independently represent NR4,
S or O; R4 represents hydrogen, C1-C5 linear or branched
alkyl or C6-C12 aryl; and R4 in the formula may be the
same or different); B represents a valence bond, C1-C14 linear
or branched alkylene (with the provisos that said alkylene is optionally
substituted by at least one substituent selected from the group
consisting of C1-C5 alkoxy, C1-C5 alkanoyloxy,
hydroxy, fluorine, chlorine, bromine, iodine, amino, nitro, cyano,
trifluoromethyl, trifluoromethoxy and phenoxy, and that 1 to 3 methylene
groups may be substituted by carbonyl group(s)), C2-C14 linear
or branched acyclic unsaturated hydrocarbon containing 1 to 3 double
bonds and/or triple bonds (with the provisos that said acyclic
unsaturated hydrocarbon is optionally substituted by at least one
substituent selected from the group consisting of C1-C5 alkoxy,
C1-C5 alkanoyloxy, hydroxy, fluorine, chlorine, bromine,
iodine, amino, nitro, cyano, trifluoromethyl, trifluoromethoxy and
phenoxy, and that 1 to 3 methylene groups may be substituted by carbonyl
group(s)) or C1-C14 linear or branched saturated or unsaturated
hydrocarbon containing 1 to 5 thioether bonds, ether bonds and/or amino
bonds (with the provisos that a hetero atom does not directly binds to A,
and that 1 to 3 methylene groups may be substituted by carbonyl
group(s)); R5 represents hydrogen or organic group having a basic
skeleton shown below (with the proviso that said organic group is
optionally substituted by at least one substituent selected from the
group consisting of C1-C5 alkyl, C1-C5 alkoxy,
C1-C5 alkanoyloxy, hydroxy, fluorine, chlorine, bromine,
iodine, amino, nitro, cyano, isothiocyanato, trifluoromethyl,
trifluoromethoxy and methylenedioxy); ##STR00006## Organic groups
represented by R5 and R6 represents hydrogen, C1-C5
alkyl or C1-C5 alkanoyl.] or a pharmacologically acceptable
acid addition salt thereof; (2) sodium thiosulfate; (3) at least one
selected from the group consisting of saccharides and sugar alcohols; and
(4) crospovidone, sodium carboxymethyl starch or a mixture thereof,
wherein the content of said (4) is 1 to 20% by weight per unit weight
containing said effective ingredient.

2. The tablet according to claim 1, wherein said (3) is at least one
selected from the group consisting of potato starch, saccharose, lactose,
mannitol, erythritol and maltitol.

3. The tablet according to claim 1, wherein a part or the entirety of
said (3) is granulated granules.

4. The tablet according to claim 3, wherein said granulated granules are
produced by extrusion granulation, stirring granulation, spray drying or
fluidized bed granulation.

5. The tablet according to claim 1, said tablet being produced by a
production method comprising the steps of dissolving or suspending said
effective ingredient in water or a pharmacologically acceptable solvent
and adding the resulting liquid to said saccharide or sugar alcohol.

6. The tablet according to claim 1, wherein said tablet is in a coated
form.

Description:

TECHNICAL FIELD

[0001] The present invention relates to a stable tablet of a
4,5-epoxymorphinan derivative or a pharmacologically acceptable acid
addition salt thereof.

BACKGROUND ART

[0002] A 4,5-epoxymorphinan derivative represented by the Formula (I)
(described later) or a pharmacologically acceptable acid addition salt
thereof, which is the effective ingredient of the present invention, has
prominent antipruritic effect and has been disclosed as a compound
effective as a therapeutic drug for pruritus in a variety of diseases
accompanying pruritus (for example, see Patent Document 1). However, the
aforementioned 4,5-epoxymorphinan derivative has been known to be
chemically unstable to light, heat and oxygen, and with regard to the
method of stabilizing such 4,5-epoxymorphinan derivative, it is described
that a stable pharmaceutical composition can be obtained by allowing the
composition to contain a saccharide(s) or sugar alcohol(s) and an
antioxidant such as sodium thiosulfate (see Patent Document 2). Yet, when
the present inventors examined tableting of the 4,5-epoxymorphinan
derivative represented by the Formula (I) or a pharmacologically
acceptable acid addition salt thereof, it was revealed that, although a
conventionally known stabilization method in which an antioxidant such as
sodium thiosulfate is added is effective for stabilization of the
effective ingredient in a liquid-form, in cases where the method is
employed for a tablet, it is difficult to obtain a tablet whose
decomposition is minimized over a long period of time in unpacked state
or in a normal package form and which maintains sufficient stability as a
tablet.

[0003] Conventionally, as a method of stabilizing various morphinan
compounds including morphine, a technique of adding a basic component to
morphine (for example, see Patent Document 3) and a method in which an
antioxidant such as sodium thiosulfate or tocopherol is combined with
naloxone (for example, see Patent Document 4), as well as a method in
which a chelating agent and a citrate buffer are added to
methylnaltrexone (for example, see Patent Document 5) and a method in
which an organic acid and a chelate forming agent are blended with
naltrexone hydrochloride (for example, see Patent Document 6), have been
disclosed. However, none of these reports includes any description with
regard to the type and the content of disintegrating agent effective in
stabilization, and the stabilization effect imparted to a tablet by a
specific disintegrating agent, crospovidone or sodium carboxymethyl
starch, has not been revealed.

[0004] Meanwhile, as a tablet which comprises a saccharide such as lactose
or a sugar alcohol such as mannitol or erythritol and, as disintegrating
agent, crospovidone or sodium carboxymethyl starch, an intraorally
disintegrating-type tablet which is intended for improving the dose
compliance and can be taken without water has been disclosed (for
example, see Patent Document 7). However, all of such reports merely
disclose a tablet which has superior intraoral quick disintegration
property along with formulation strength at a level which does not pose a
problem in handling, and the stabilization effect imparted by
crospovidone or sodium carboxymethyl starch has not been reported.

[0005] In addition, as a method of stabilizing a drug by blending
crospovidone or sodium carboxymethyl starch, there are reports that fast
release property is attained and drug hydrolysis is suppressed by
blending crospovidone with sarpogrelate hydrochloride (see Patent
Document 8); that a preparation which has both disintegration property
and tablet hardness, as well as excellent storage stability over a long
period of time, is attained by blending crospovidone or sodium
carboxymethyl starch with iguratimod (see Patent Document 9); and that
the stability is improved by blending crospovidone with vitamin or the
like (for example, see Patent Document 10 and Non-patent Document 1).
However, needless to say, since the mechanism of drug destabilization is
largely dependent on the chemical structure and physiochemical properties
of the drug, these reports offer no suggestion with regard to the
stability of the effective ingredient of the present invention, which is
a 4,5-epoxymorphinan derivative represented by the Formula (I) or a
pharmacologically acceptable acid addition salt thereof.

[0017] An object of the present invention is to provide a stable tablet
comprising a 4,5-epoxymorphinan derivative or a pharmacologically
acceptable acid addition salt thereof as an effective ingredient.

Means for Solving the Problems

[0018] In order to develop a stable tablet capable of enduring in unpacked
state and long-term storage, the present inventors intensively studied to
discover that, among those disintegrating agents commonly used for
formulation, only crospovidone and sodium carboxymethyl starch can, when
made to co-exist with sodium thiosulfate and a saccharide or sugar
alcohol, allow a 4,5-epoxymorphinan derivative or a pharmacologically
acceptable acid addition salt thereof to more stably exist in a tablet,
thereby completing the present invention.

[0019] That is, the present invention relates to the following inventions.

[1] A tablet comprising the following (1) to (4): (1) as an effective
ingredient, a 4,5-epoxymorphinan derivative represented by the Formula
(I) (described later) or a pharmacologically acceptable acid addition
salt thereof; (2) sodium thiosulfate; (3) at least one selected from the
group consisting of saccharides and sugar alcohols; and (4) crospovidone,
sodium carboxymethyl starch or a mixture thereof, in which tablet the
content of the aforementioned (4) is 1 to 20% by weight per unit weight
containing the aforementioned effective ingredient. [2] The tablet
according to [1], wherein the aforementioned (3) is at least one selected
from the group consisting of potato starch, saccharose, lactose,
mannitol, erythritol and maltitol. [3] The tablet according to [1] or
[2], wherein a part or the entirety of the aforementioned (3) is
granulated granules. [4] The tablet according to [3], wherein the
aforementioned granulated granules are produced by extrusion granulation,
stirring granulation, spray drying or fluidized bed granulation. [5] The
tablet according to any one of [1] to [4], the tablet being produced by a
production method comprising the steps of dissolving or suspending the
aforementioned effective ingredient in water or a pharmacologically
acceptable solvent and adding the resulting liquid to the aforementioned
saccharide or sugar alcohol. [6] The tablet according to any one of [1]
to [5], wherein the tablet is in a coated form.

EFFECTS OF THE INVENTION

[0020] By allowing a tablet to comprise, as the effective ingredient, a
4,5-epoxymorphinan derivative represented by the Formula (I) (described
later) of the present invention or a pharmacologically acceptable acid
addition salt thereof and blending thereto crospovidone or sodium
carboxymethyl starch in a prescribed amount, a fast-disintegrating tablet
or an intraorally disintegrating tablet which has superior storage
stability and remains highly stable even after a long time since its
production can also be produced.

MODE FOR CARRYING OUT THE INVENTION

[0021] The tablet according to the present invention will now be
described. The indispensable components of the tablet according to the
present invention are:

(1) a 4,5-epoxymorphinan derivative represented by the Formula (I)
(described later) or a pharmacologically acceptable acid addition salt
thereof (effective ingredient); (2) sodium thiosulfate; (3) at least one
selected from the group consisting of saccharides and sugar alcohols; and
(4) crospovidone, sodium carboxymethyl starch or a mixture thereof. The
component (4) is contained in an amount of 1 to 20% by weight per unit
weight containing the effective ingredient. The phrase "unit containing
the effective ingredient" used herein refers to a solid component unit
directly in contact with the effective ingredient in the preparation, and
in the case of a film-coated tablet, it refers to the core of the tablet,
which is an essential part affecting the drug stability. The phrase "% by
weight per unit weight containing the effective ingredient" used herein
means a weight percentage with respect to the weight of the solid
component unit directly in contact with the effective ingredient in the
preparation. A tablet comprising the components (2) to (4) has a reduced
decomposition of the effective ingredient (1) and stably comprises the
effective ingredient even after a long period of time. The stability of
the effective ingredient in a tablet can be evaluated by, for example,
leaving the tablet to stand in an open state under the condition of
40° C./75% RH, which is the acceleration condition described in
the Drug Approval and Licensing Procedures in Japan (2006), and
subsequently measuring the residual ratio of the effective ingredient in
the tablet by HPLC method or the like.

[0022] The indispensable component (1) of the tablet according to the
present invention is a 4,5-epoxymorphinan derivative represented by the
following Formula (I) or a pharmacologically acceptable acid addition
salt thereof

##STR00001##

[0023] Here, in the Formula (I), the double line composed of a dashed line
and a solid line represents a double bond or a single bond; R' represents
C1-C5 alkyl, C4-C7 cycloalkylalkyl, C5-C7
cycloalkenylalkyl, C6-C12 aryl, C7-C13 aralkyl,
C4-C7 alkenyl, allyl, C1-C5 furan-2-ylalkyl or
C1-C5 thiophen-2-ylalkyl; R2 represents hydrogen, hydroxy,
nitro, C1-C5 alkanoyloxy, C1-C5 alkoxy,
C1-C5 alkyl or --NR7R8; R7 represents hydrogen
or C1-C5 alkyl; R8 represents hydrogen, C1-C5
alkyl or --C(═O)R9; R9 represents hydrogen, phenyl or
C1-C5 alkyl; R3 represents hydrogen, hydroxy,
C1-C5 alkanoyloxy or C1-C5 alkoxy; A represents
--N(R4)C(═X)--, N(R4)C(═X)Y--, --N(R4)-- or
--N(R4)SO2-- (wherein X and Y independently represent NR4,
S or O; R4 represents hydrogen, C1-C5 linear or branched
alkyl or C6-C12 aryl; and R4 in the formula may be the
same or different); B represents a valence bond or C1-C14
linear or branched alkylene (with the provisos that the alkylene is
optionally substituted by at least one substituent selected from the
group consisting of C1-C5 alkoxy, C1-C5 alkanoyloxy,
hydroxy, fluorine, chlorine, bromine, iodine, amino, nitro, cyano,
trifluoromethyl, trifluoromethoxy and phenoxy, and that 1 to 3 methylene
groups may be substituted by carbonyl group(s)), C2-C14 linear
or branched acyclic unsaturated hydrocarbon containing 1 to 3 double
bonds and/or triple bonds (with the provisos that the acyclic unsaturated
hydrocarbon is optionally substituted by at least one substituent
selected from the group consisting of C1-C5 alkoxy,
C1-C5 alkanoyloxy, hydroxy, fluorine, chlorine, bromine,
iodine, amino, nitro, cyano, trifluoromethyl, trifluoromethoxy and
phenoxy, and that 1 to 3 methylene groups may be substituted by carbonyl
group(s)) or C1-C14 linear or branched saturated or unsaturated
hydrocarbon containing 1 to 5 thioether bonds, ether bonds and/or amino
bonds (with the provisos that a hetero atom does not directly binds to A,
and that 1 to 3 methylene groups may be substituted by carbonyl
group(s)); and R5 represents hydrogen or an organic group having a
basic skeleton shown below (with the proviso that the organic group is
optionally substituted by at least one substituent selected from the
group consisting of C1-C5 alkyl, C1-C5 alkoxy,
C1-C5 alkanoyloxy, hydroxy, fluorine, chlorine, bromine,
iodine, amino, nitro, cyano, isothiocyanato, trifluoromethyl,
trifluoromethoxy and methylenedioxy).

##STR00002## [0024] Organic groups represented by R5

[0025] R6 represents hydrogen, C1-C5 alkyl or
C1-C5 alkanoyl.

[0026] The double line composed of a dashed line and a solid line in the
Formula (I) represents, as described in the above, a double bond or a
single bond; however, it is preferably a single bond.

[0028] It is preferred that R2 and R3 independently be hydrogen,
hydroxy, acetoxy or methoxy.

[0029] It is preferred that A be --N(R4)C(═O)--,
--N(R4)C(═O)O--, --N(R4)-- or --N(R4)SO2--
(wherein R4 represents hydrogen or C1-C5 linear or
branched alkyl), and preferred thereamong is --N(R4)C(═O)-- or
--N(R4)C(═O)O-- (wherein R4 represents hydrogen or
C1-C5 linear or branched alkyl).

[0030] It is preferred that B be C1-C3 linear alkylene,
--CH═CH--, --C≡C--, --CH2O-- or --CH2S--, and
preferred thereamong is C1-C3 linear alkylene, --CH═CH-- or
--C≡C--.

[0031] It is preferred that R5 be hydrogen or an organic group having
a basic skeleton shown below (with the proviso that the organic group is
optionally substituted by at least one substituent selected from the
group consisting of C1-C5 alkyl, C1-C5 alkoxy,
C1-C5 alkanoyloxy, hydroxy, fluorine, chlorine, bromine,
iodine, amino, nitro, cyano, isothiocyanato, trifluoromethyl,
trifluoromethoxy and methylenedioxy).

[0035] In the present invention, particularly preferred as the
4,5-epoxymorphinan derivative represented by the Formula (I) or a
pharmacologically acceptable salt thereof are
17-(cyclopropylmethyl)-3,14β-dihydroxy-4,5α-epoxy-6β-[N-m-
ethyl-trans-3-(3-furyl)acrylamido]morphinan hydrochloric acid salt
(hereinafter, referred to as Compound 1) and
17-(cyclopropylmethyl)-3,14β-dihydroxy-4,5α-epoxy-6β-[N-m-
ethyl-3-(4-trifluoromethylphenyl)propiolamido]morphinan hydrochloric acid
salt (hereinafter, referred to as Compound 2).

##STR00004##

[0036] The 4,5-epoxymorphinan derivative or a pharmacologically acceptable
acid addition salt thereof, which is the medicinal component in the
tablet of the present invention, can be produced, for example, in
accordance with the method described in Japanese Patent No. 2525552 or WO
93/15081.

[0037] The content of the 4,5-epoxymorphinan derivative or a
pharmacologically acceptable acid addition salt thereof, which is the
medicinal component in the tablet of the present invention, is not
particularly restricted as long as it is a therapeutically effective
amount. For example, it can be in the range of 0.01 to 10,000
μg/preparation, and it is usually in the range of 0.1 to 1,000
μg/preparation.

[0038] The indispensable component (2) of the tablet according to the
present invention is sodium thiosulfate. As sodium thiosulfate used in
the present invention, any of the generally commercially available ones
may be employed. Sodium thiosulfate may be an anhydride or a hydrate
(pentahydrate); however, it is preferably a hydrate. The content thereof
may be any amount as long as it is not greater than 5% by weight per unit
weight containing the effective ingredient; however, it is preferably not
greater than 0.5% by weight. The lower limit of the content is not
particularly restricted; however, it is usually not less than 0.00001% by
weight per unit weight containing the effective ingredient.

[0039] The indispensable component (3) of the tablet according to the
present invention is at least one selected from the group consisting of
saccharides and sugar alcohols. As the saccharide and/or sugar alcohol
used in the present invention, any of the generally commercially
available ones may be employed. Examples of the saccharide and/or sugar
alcohol include potato starch, saccharose, lactose, mannitol, erythritol
and maltitol, and preferred thereamong is mannitol. In the present
invention, as the indispensable component (3), the saccharide and sugar
alcohol may be used individually or two or more thereof may be used in
combination. The content thereof is not particularly restricted; however,
with respect to the unit weight of the preparation containing the
effective ingredient, it is usually not less than 75% by weight and may
be any amount not less than 80% by weight, and it is preferably not less
than 85% by weight, more preferably not less than 90% by weight. Further,
the particle form of the saccharide and/or sugar alcohol used is not
particularly restricted and it may be granulated granules, powder, fine
powder; however, from the standpoint of the advantage in handling, it is
preferred that the saccharide and/or sugar alcohol be in the form of
granulated granules in its partial or the entire amount. In the present
invention, the term, the saccharide and/or sugar alcohol which is/are the
indispensable component (3) "is/are partially or entirely in the form of
granulated granules", means either of the followings: to prepare the
tablet of the present invention by mixing a part of or the entirety of
the saccharide and/or sugar alcohol in the form of granulated granules
with other raw material(s); and to, after mixing a part of or the
entirety of the saccharide and/or sugar alcohol in the form of powder
with (a partial or the entire amount of) other raw material(s), granulate
the resulting mixture into granules to subsequently prepare therefrom the
tablet of the present invention. In the former case, commercially
available granulated granule may be used or granulated granule prepared
from powder-form saccharide and/or sugar alcohol may also be used.
Examples of powder mannitol include PEARLITOL (registered trademark) 50C
manufactured by Roquette Japan K.K. Meanwhile, as the granulated granule,
those produced by any of the known techniques such as spray drying,
extrusion granulation, stirring granulation and fluidized bed granulation
may also be used. Spray-dried granules or extrusion-granulated granules
are preferably used since no tableting problem occurs and high tablet
hardness can be attained. Examples of known mannitol granulated granules
include spray-dried granule PEARLITOL (registered trademark) 200SD and
extrusion-granulated granule PEARLITOL (registered trademark) 300DC, both
of which are manufactured by Roquette Japan K.K. In addition, when the
particle diameter of the saccharide or sugar alcohol is small, tableting
problem easily occurs and when the particle diameter is large, high
tablet hardness is not likely to be attained; therefore, for example, an
average particle diameter may be, when measured in accordance with the
particle size measurement method described in the Japanese Pharmacopeia
15th Edition, not less than 10 μm, and it is preferably not less than
30 μm, more preferably not less than 50 μm. Further, the upper
limit of the particle diameter is usually not greater than 3,000 μm,
particularly 1,000 μm; however, it is not restricted thereto.

[0040] The indispensable component (4) of the tablet according to the
present invention is crospovidone, sodium carboxymethyl starch or a
mixture thereof. As the crospovidone or sodium carboxymethyl starch used
in the present invention, any of the generally commercially available
ones may be employed. Examples of specific commercial products of
crospovidone include Kollidon (registered trademark) CL, CL-M, CL-F and
CL-SF which are manufactured by BASF, as well as Polyplasdone XL, XL-10
and INF-10 which are manufactured by IPS Ltd. Examples of specific
commercial products of sodium carboxymethyl starch include Explotab
(registered trademark) and VIVASTAR (registered trademark) manufactured
by JRS, Primojel (registered trademark) manufactured by DMV, and Glycolys
(registered trademark) manufactured by Roquette Japan K.K. The content of
crospovidone or sodium carboxymethyl starch (the total amount when a
mixture thereof is used) may be 1 to 20% by weight per unit weight
containing the above-described effective ingredient. In order to ensure
better quality and performance of the tablet, the content may be
preferably in the range of 2 to 15% by weight, more preferably 5 to 10%
by weight.

[0041] In the tablet according to the present invention, in addition to
the indispensable components (1) to (4) described in the above, a
pharmacologically acceptable additive such as lubricant, flavoring agent
or coloring agent may also be added as required. Examples of the
lubricant include magnesium stearate, calcium stearate, talc, stearic
acid, sucrose fatty acid ester and light anhydrous silicic acid.

[0042] In the tablet according to the present invention, in addition to
the indispensable components (1) to (4) described in the above, a
pharmacologically acceptable vehicle, disintegrating agent or binding
agent may also be added as required. For example, xylitol, sorbitol,
low-substituted hydroxypropyl cellulose, crystalline cellulose,
hydroxypropyl cellulose, partially-pregelatinized starch, croscarmellose
sodium, carboxymethyl cellulose or the like may also be added as
appropriate.

[0043] The tablet according to the present invention can be produced in
accordance with a known method by using the above-described indispensable
components and arbitrary components (which include those having a role as
a vehicle). The term "tablet" used herein also encompasses, in addition
to those conventional tablets taken with water, fast-disintegrating
tablets such as one described in WO 2006-038661 which have extremely
quick disintegration property and can be normally disintegrated
intraorally within one minute only with an extremely small amount of
water content such as saliva, as well as intraorally-disintegrating
tablets such as one described in Patricia Van Arnum, "Advancing ODT
Technology", Pharmaceutical Technology, Vol. 3, No. 10 pp. 66-76, 2007
(published on Oct. 2, 2007), which are normally disintegrated and
dissolved intraorally without water within 60 seconds.

[0044] The tablet according to the present invention cay be produced by a
wet granulation method comprising the steps of dissolving or suspending
the above-described effective ingredient (1) in water or a
pharmacologically acceptable solvent and adding the resulting liquid
(solution or suspension) to the saccharide or sugar alcohol. The addition
of sodium thiosulfate or that of crospovidone or sodium carboxymethyl
starch can be carried out by an arbitrary step. For example, sodium
thiosulfate may be dissolved or suspended together with the effective
ingredient in water or a pharmacologically acceptable solvent and then
added to the saccharide or sugar alcohol. Crospovidone and/or sodium
carboxymethyl starch may also be dissolved or suspended together with the
effective ingredient in water or pharmacologically acceptable solvent and
then added to the saccharide or sugar alcohol. Alternatively,
crospovidone and/or sodium carboxymethyl starch may be added after adding
sodium thiosulfate and the effective ingredient to the saccharide or
sugar alcohol and appropriately subjecting the resultant to granulation
or size selection. Further, the entire amount of the saccharide or sugar
alcohol may be added in the aforementioned step of adding the effective
ingredient, or only a partial amount of the saccharide or sugar alcohol
may be used in the step, adding the remaining amount in a later step.

[0045] In the wet granulation, a commonly used apparatus is employed, and
examples thereof include fluidized bed granulators, tumbling fluidized
bed granulators, stirring granulators, cylindrical extrusion granulators
and wet extrusion granulators. In cases where water is used as the
solvent for dissolving or suspending the effective ingredient, a
fluidized bed granulator and a tumbling fluidized bed granulator capable
of drying with spraying are suitable. Further, in cases where a volatile
solvent such as ethanol is used as the solvent for dissolving or
suspending the effective ingredient, a fluidized bed granulator, a
tumbling fluidized bed granulator and a stirring granulator are suitable.

[0046] As the apparatus for mixing the preparation, a commonly used
apparatus is employed, and examples thereof include V-shaped mixers,
ribbon mixers and air blenders.

[0047] For compression molding, a commonly used apparatus is employed, and
examples thereof include single-punch tableting machines and rotary
tableting machines. The molding pressure in tableting is not particularly
restricted and may be any pressure as long as the resulting tablet has
such a tablet hardness that would not be an issue in handling. For
example, the tableting pressure may be set at 200 to 10,000 kgf/cm2,
preferably 500 to 5,000 kgf/cm2.

[0048] The amount of the lubricant to be added is not particularly
restricted; however, for example, in the case of magnesium stearate, the
amount is preferably about 0.1 to 5.0% by weight, more preferably 0.5 to
3.0% by weight per unit weight containing the effective ingredient.

[0049] The thus obtained tablet according to the present invention
comprising a morphinan derivative represented by the Formula (I) or a
pharmacologically acceptable acid addition salt thereof as the effective
ingredient can be made into a coated preparation by adding a coating
agent as required. As the coating agent, a functional base may be
selected in accordance with the purpose and, for example, any of the
generally commercially available ones, such as hydroxypropylmethyl
cellulose, ethyl cellulose, carboxymethylethyl cellulose and premixed
products thereof, may be used.

[0050] For film coating operation, a commonly used apparatus is employed,
and a pan coating machine is suitable for producing film-coated tablets.

EXAMPLES

[0051] In order to clarify the superior effects of the present invention,
the present invention will now be explained by way of examples thereof;
however, the present invention is not restricted thereto. It is noted
here that, in the following examples, PEARLITOL (registered trademark)
200SD which is a spray-dried granule of mannitol, PEARLITOL (registered
trademark) 300DC which is a extrusion-granulated granule of mannitol and
PEARLITOL (registered trademark) 50C which is a powder-form mannitol are
abbreviated as "mannitol SD", "mannitol DC" and "mannitol C",
respectively (all of these products are manufactured by Roquette Japan
K.K.). Further, the "Compound 1" is, as stated in the above,
17-(cyclopropylmethyl)-3,14β-dihydroxy-4,5α-epoxy-6β-[N-m-
ethyl-trans-3-(3-furyl)acrylamido]morphinan hydrochloric acid salt

Example 1

[0052] Mannitol SD was weighed in an amount of 126.645 parts by weight
(hereinafter, abbreviated as "parts" and the same applies in the
followings unless otherwise specified). It was then sieved through a mesh
having 1 mm openings and placed into a mortar. The thus obtained granules
were mixed for 5 minutes in the mortar while spraying thereto a spray
solution in which 0.005 parts of the Compound 1 and 0.1 parts of sodium
thiosulfate hydrate (Kokusan Chemical Co., Ltd.) were dissolved in
distilled water. The resultant was dried at 45° C. for 2 hours
using a hot-air dryer (PS-212, Espec Corporation) to produce granulated
granules. The granulated granules were subjected to size selection using
a comil (197S, Powrex Corporation) and added with 2.6 parts of
crospovidone (Kollidon (registered trademark) CL, BASF), and the
resultant was mixed for 15 minutes using a V-shaped mixer (Tsutsui
Scientific Instruments Co., Ltd.). To the thus obtained mixture, 0.65
parts of magnesium stearate (Taihei Chemical Industrial Co., Ltd.) was
further added, and the resultant was mixed for 5 minutes. The thus
obtained granules were made into a tablet of 130 mg using a tableting
machine (Correct 19, Kikusui Seisakusho Ltd.).

Example 2

[0053] Mannitol SD was weighed in an amount of 38.475 parts, sieved
through a mesh having 1 mm openings and loaded into a fluidized bed
granulator (FLO-5, Freund Corporation). A spray solution in which 0.005
parts of the Compound 1 and 0.1 parts of sodium thiosulfate hydrate were
dissolved in distilled water was sprayed to the thus obtained granules to
produce granulated granules. The granulated granules were processed using
the comil to obtain size-selected granules. To 38.58 parts of the thus
obtained size-selected granules, 84.27 parts of mannitol SD and 6.5 parts
of crospovidone were added, and the resultant was mixed for 15 minutes
using the V-shaped mixer. To the thus obtained mixture, 0.65 parts of
magnesium stearate (Taihei Chemical Industrial Co., Ltd.) was further
added, and the resultant was mixed for 5 minutes. The thus obtained
granules were made into a tablet of 130 mg using a tableting machine
(Correct 19, Kikusui Seisakusho Ltd.).

Example 3

[0054] A tablet was produced in the same manner as in Example 2, except
that mannitol SD and crospovidone were added in an amount of 77.77 parts
and 13 parts, respectively, to 38.58 parts of the size-selected granules
of Example 2.

Example 4

[0055] A tablet was produced in the same manner as in Example 2, except
that mannitol SD and crospovidone were added in an amount of 71.27 parts
and 19.5 parts, respectively, to 38.58 parts of the size-selected
granules of Example 2.

Example 5

[0056] A tablet was produced in the same manner as in Example 1, except
that the content of mannitol SD of Example 1 was 103.245 parts and that
of crospovidone was 26 parts.

Example 6

[0057] Mannitol SD was weighed in an amount of 96.745 parts, sieved
through a mesh having 1 mm openings and loaded into a fluidized bed
granulator (FLO-5, Freund Corporation). A spray solution in which 0.005
parts of the Compound 1 and 0.1 parts of sodium thiosulfate hydrate were
dissolved in distilled water was sprayed to the thus obtained granules to
produce granulated granules. Next, mannitol C was weighed in an amount of
26 parts, sieved through a mesh having 1 mm openings and, along with 6.5
parts of crospovidone, loaded into a stirring granulator (NMG-3L, Nara
Machinery Co., Ltd.). Subsequently, the thus loaded mixture was
granulated while adding thereto distilled water to produce granules. The
granulated granules produced by the fluidized bed granulator and those
produced by the stirring granulator were respectively processed using the
comil to obtain size-selected granules. To 129.35 parts of the thus
size-selected granules, 0.65 parts of magnesium stearate (Taihei Chemical
Industrial Co., Ltd.) was added, and the resultant was mixed for 5
minutes. The thus obtained granules were made into a tablet of 130 mg
using a tableting machine (Correct 19, Kikusui Seisakusho Ltd.).

Example 7

[0058] A tablet was produced in the same manner as in Example 1, except
that mannitol SD of Example 1 was replaced with different grade
mannitols, mannitol DC and mannitol C, in an amount of 96.745 parts and
26 parts, respectively, and that the content of crospovidone was 6.5
parts.

Example 8

[0059] A tablet was produced in the same manner as in Example 1, except
that mannitol SD of Example 1 was replaced with lactose (Pharmatose
(registered trademark) 200M, DMV) in an amount of 122.095 parts and that
the contents of crospovidone and magnesium stearate were 6.5 parts and
1.3 parts, respectively.

Example 9

[0060] A tablet was produced in the same manner as in Example 1, except
that mannitol SD of Example 1 was partially replaced with erythritol
(Nikken Chemical Laboratory Co., Ltd.) in such a manner that the contents
of mannitol SD and erythritol were 83.095 parts and 39 parts,
respectively, and that the contents of crospovidone and magnesium
stearate were 6.5 parts and 1.3 parts, respectively.

Example 10

[0061] A tablet was produced in the same manner as in Example 1, except
that mannitol SD of Example 1 was partially replaced with potato starch
(ST-P, Nippon Starch Chemical Co., Ltd.) in such a manner that the
contents of mannitol SD and potato starch were 83.095 parts and 39 parts,
respectively, and that the contents of crospovidone and magnesium
stearate were 6.5 parts and 1.3 parts, respectively.

Example 11

[0062] A tablet was produced in the same manner as in Example 1, except
that mannitol SD of Example 1 was replaced with maltitol (powder maltitol
G-3, Towa-Kasei Co., Ltd.) in an amount of 122.095 parts and that the
contents of crospovidone and magnesium stearate were 6.5 parts and 1.3
parts, respectively.

Example 12

[0063] A tablet was produced in the same manner as in Example 1, except
that mannitol SD of Example 1 was replaced with saccharose (Suzu Funmatsu
Yakuhin K.K.) in an amount of 122.095 parts and that the contents of
crospovidone and magnesium stearate were 6.5 parts and 1.3 parts,
respectively.

Example 13

[0064] A tablet was produced in the same manner as in Example 2, except
that mannitol SD and sodium carboxymethyl starch (EXPLOTAB (registered
trademark), JRS Pharma) were added in an amount of 88.17 parts and 2.6
parts, respectively, to 38.58 parts of the size-selected granules of
Example 2.

Example 14

[0065] A tablet was produced in the same manner as in Example 1, except
that the content of mannitol SD of Example 1 was 116.245 parts and that
crospovidone was replaced with sodium carboxymethyl starch in an amount
of 13 parts.

Example 15

[0066] A tablet was produced in the same manner as in Example 1, except
that the content of mannitol SD of Example 1 was 116.245 parts and that
crospovidone was partially replaced with sodium carboxymethyl starch in
such a manner that the contents of crospovidone and sodium carboxymethyl
starch were both 6.5 parts each.

Comparative Example 1

[0067] Weighed in a standard bottle were 10 parts by weight of the
Compound 1 and 100 parts of crystalline cellulose (Avicel (registered
trademark) PH-101, Asahi Kasei Corporation). Distilled water in an amount
of 30 parts was added thereto and the resultant was mixed with a glass
rod. After drying the thus obtained granules, the dried granules were
made into a tablet of 100 mg using a single-punch tableting machine
(RIKEN POWER, Riken Seiki Co., Ltd.).

Comparative Example 2

[0068] A tablet was produced in the same manner as in Comparative Example
1, except that crystalline cellulose of Comparative Example 1 was
replaced with polyvinyl alcohol (PVA EG-5, Nippon Synthetic Chemical
Industry Co., Ltd.).

Comparative Example 3

[0069] A tablet was produced in the same manner as in Comparative Example
1, except that crystalline cellulose of Comparative Example 1 was
replaced with hydroxypropyl cellulose (HPC-L (registered trademark),
Nippon Soda Co., Ltd.).

Comparative Example 4

[0070] A tablet was produced in the same manner as in Comparative Example
1, except that crystalline cellulose of Comparative Example 1 was
replaced with croscarmellose sodium (Ac-di-sol (registered trademark),
FMC Bio Polymer) (hereinafter, abbreviated as Ac-di-sol).

Comparative Example 5

[0071] A tablet was produced in the same manner as in Comparative Example
1, except that crystalline cellulose of Comparative Example 1 was
replaced with carmellose calcium (CMC-Ca ECG-505, Gotoku Chemical Co.,
Ltd.) (hereinafter, abbreviated as CMC-Ca).

Comparative Example 6

[0072] A solid preparation was produced in accordance with the technique
described in WO 99/02158 (Patent Document 2). Lactose and crystalline
cellulose were weighed in an amount of 49.91 parts and 26.4 parts,
respectively, and loaded into the fluidized bed granulator. A spray
solution in which 0.01 parts of the Compound 1, 0.08 parts of sodium
thiosulfate hydrate and 3.2 parts of hydroxypropyl cellulose (HPC-SL
(registered trademark), Nippon Soda Co., Ltd.) were dissolved in
distilled water was sprayed to the thus obtained formulation powder to
produce granulated granules. The granulated granules were processed using
the comil to obtain size-selected granules. To 79.6 parts of the thus
obtained size-selected granules, 0.4 parts of magnesium stearate was
added, and the resultant was mixed for 5 minutes. The thus obtained
granules were made into a tablet of 80 mg using the tableting machine.

Comparative Example 7

[0073] Mannitol SD was weighed in an amount of 78.895 parts, sieved
through a mesh having 1 mm openings and loaded into a fluidized bed
granulator (FLO-5, Freund Corporation). A spray solution in which 0.005
parts of the Compound 1 and 0.1 parts of sodium thiosulfate hydrate were
dissolved in distilled water was sprayed to the thus obtained granules to
produce drug-carrying granules. To 79 parts of the thus obtained
drug-carrying granules, 15 parts of mannitol SD and 5 parts of Ac-di-sol
were added, and the resultant was mixed for 15 minutes using a V-shaped
mixer (permeation-mode S-5, Tsutsui Scientific Instruments Co., Ltd.). To
the thus obtained mixture, 1 part of magnesium stearate was further
added, and the resultant was mixed for 5 minutes. The thus obtained
granules were made into a tablet of 100 mg using the tableting machine.

Comparative Example 8

[0074] Drug-carrying granules were prepared in the same manner as in
Comparative Example 7, and the subsequent mixing and tableting were
carried out in the same manner as in Comparative Example 7, except that
10 parts of mannitol SD and 10 parts of CMC-Ca in place of Ac-di-sol were
added to 79 parts of the drug-carrying granules.

Comparative Example 9

[0075] A tablet was produced in the same manner as in Example 1, except
that the content of mannitol SD was 90.245 parts and that of crospovidone
was 39 parts.

Comparative Example 10

[0076] A tablet was produced in the same manner as in Example 1, except
that the content of mannitol SD was 77.245 parts and that of crospovidone
was 52 parts.

Comparative Example 11

[0077] A tablet was produced in the same manner as in Example 2, except
that the content of mannitol SD was 122.845 parts and that sodium
thiosulfate hydrate was not added.

Example 16

[0078] The tablets obtained in each of Examples 1 to 15 and Comparative
Examples 1 to 11 were left to stand in an open state under the condition
of 40° C./75% RH, which is the acceleration condition described in
the Drug Approval and Licensing Procedures in Japan (2006), and the
residual ratio (%) of the drug was subsequently measured by HPLC method
to evaluate the stability thereof (Tables 1 and 2).

[0079] As shown in Tables 1 and 2, for Comparative Example 6 in which
saccharide and sodium thiosulfate were blended without crospovidone and
for Comparative Example 11 in which sugar alcohol and crospovidone were
blended without sodium thiosulfate, the drug residual ratio was measured
to be low at 94.4% and 83.3%, respectively. In addition, Comparative
Examples 1 to 5, 7 and 8 in which crospovidone or sodium carboxymethyl
starch was not blended and Comparative Examples 9 and 10 in which the
content of crospovidone was not less than 30% also exhibited low residual
ratios. In contrast, those tablets described in Examples 1 to 15, which
comprise sodium thiosulfate, saccharide or sugar alcohol, and 1 to 20% by
weight of crospovidone, sodium carboxymethyl starch or a mixture thereof
per unit weight containing the effective ingredient, all exhibited a
residual ratio of not less than 96% even when they were stored unpacked
for one month under the condition of 40° C. and 75% RH, and showed
a prominent stabilization effect as compared to the formulations of
Comparative Examples; therefore, it was demonstrated that those tablets
of Examples 1 to 15 can ensure sufficient stability also when handled as
a pharmaceutical.

[0080] Mannitol SD was weighed in an amount of 38.475 parts, sieved
through a mesh having 1 mm openings and loaded into the fluidized bed
granulator. Then, a spray solution in which 0.005 parts of the Compound 1
and 0.1 parts of sodium thiosulfate hydrate were dissolved in distilled
water was sprayed to the thus obtained granules to produce granulated
granules. The granulated granules were processed using the comil to
obtain size-selected granules. To 38.58 parts of the thus obtained
size-selected granules, 84.27 parts of mannitol SD and 6.5 parts of
crospovidone were added, and the resultant was mixed for 15 minutes using
the V-shaped mixer. To the thus obtained mixture, 0.65 parts of magnesium
stearate (Taihei Chemical Industrial Co., Ltd.) was further added, and
the resultant was mixed for 5 minutes. The thus obtained granules were
made into a tablet of 130 mg using a tableting machine (Correct 19,
Kikusui Seisakusho Ltd.). Next, this tablet was loaded into a film
coating machine (Hicoater Mini, Freund Corporation) and a solution in
which OPADRY-OY7300 (Japan Colorcon) was dissolved or dispersed was
sprayed to the tablet to produce a coated tablet of 137 mg in which 7 mg
of coating agent was added to 130 mg of the tablet.

Example 18

[0081] Mannitol DC was weighed in an amount of 96.745 parts, sieved
through a mesh having 1 mm openings and loaded into the fluidized bed
granulator. Then, a spray solution in which 0.005 parts of the Compound 1
and 0.1 parts of sodium thiosulfate hydrate were dissolved in distilled
water was sprayed to the thus obtained granules to produce granulated
granules. Then, mannitol C was weighed in an amount of 25.9675 parts,
sieved through a mesh having 1 mm openings and, along with 6.5 parts of
crospovidone, loaded into the stirring granulator. Subsequently, the thus
loaded mixture was granulated while adding thereto distilled water into
which 0.0325 parts of iron sesquioxide was dispersed, thereby producing
granulated granules. The granulated granules produced by the fluidized
bed granulator and those produced by the stirring granulator were
respectively processed using the comil to obtain size-selected granules.
To 129.35 parts of the thus size-selected granules, 0.65 parts of
magnesium stearate was added, and the resultant was mixed for 5 minutes.
The thus obtained granules were made into a WR tablet of 130 mg using the
tableting machine.

Example 19

[0082] For the tablet obtained in Example 18, the intraoral disintegration
time in three subjects consisting of a healthy adult male and female was
measured. The time required for the tablet to be completely disintegrated
by saliva without taking water into the mouth and chewing the tablet (the
time required for the subject to no longer have a feel of foreign matter
in the mouth) was measured, and the average of the measurements for the
three subjects was used as the intraoral disintegration time. As the
result, the intraoral disintegration time was approximately 9 seconds;
therefore, it was confirmed that the tablet has excellent disintegration
property.